Chapter 280 - Heart Failure: Management Flashcards Preview

Cardiology > Chapter 280 - Heart Failure: Management > Flashcards

Flashcards in Chapter 280 - Heart Failure: Management Deck (73)

Name the therapies that are considered disease-modifying in those with heart failure (HF) with reduced ejection fraction (HFrEF).

"Early management evolved from symptom control to disease-modifying therapy in HFrEF with the advent of renin-angiotensin-aldosterone system-directed therapy, beta receptor antagonists, mineralocorticoid receptor antagonists, resynchronization therapy, and implantable cardio-defibrillators."


Therapeutic advantagens in those with HF with preserved ejection fraction (HFpEF) and acute decompensated HF (ADHF) have remainded devoided of convincing therapeutic advances to alter their natural history.
True or False?



Compare the clinical features and outcomes in those with advanced HF to those with early-stage asymptomatic left ventricle (LV) dysfunction.

"In advanced heart failure, a stage of disease typically encountered in HFrEF, the patient remains markedly symptomatic with demonstrated refractoriness or inability to tolerate full-dose neurohormonal antagonism, often requires escalating doses of diuretics, and exhibits persistent hyponatremia and renal insufficiency with frequent episodes of heart failure decompensation requiring recurrent hospitalizations. Such individuals are at the highest risk of sudden or progressive pump failure-related deaths. In contrast, early-stage asymptomatic left ventricular dysfunction is amenable to preventive care, and its natural history is modifiable by neurohormonal antagonism."


Regarding those with HFpEF, addressing surrogate targets, such as regression of ventricular hypertrophy in hypertensive heart disease, and use of lusitropic agents, such as calcium channel blockers and beta receptor antagonists, have been disappointing. Experience has demonstrated that lowering blood pressure alleviates symptoms more effectively than targeted therapy with specific agents.
True or False?



Summarize the evidence on therapeutics for HFpEF, namely the main results of the CHARM, I-PRESERVE, DIG, and SENIORS trials. Also, discuss the evidence regarding the use of ACE inhibitors in those with HFpEF.

"The Candesartan in Heart Failure-Assessment of Mortality and Morbidity (CHARM) Preserved study showed a statistically significant reduction in hostapilizations but no difference in all-cause mortaity in patients with HFpEF who were treated with the angiotensin receptor blocker, candesartan. Similarly, the Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) trial demonstrated no differences in meaningful endpoints in such patients treated with irbesartan. An earlier analysis of a subset of the Digitalis Investigation Group (DIG) trial found no role for digoxin in the treament of HFpEF. In the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure (SENIORS) trial of nebivolol, a vasodilating beta blocker, the subgroup of elderly patients with prior hostapilization and HFpEF did not appear to benefit in terms of all-cause or cardiovascular mortality. Much smaller mechanistic studies in the elderly with the angiotensin-converting enzyme inhibitor enalapril showed no effect on peak exercise oxygen consumption, 6-minute walk distance, aortic distensibility, left ventricular mass, or peripheral neurohormone expression."


What are the main findings of the RELAX trial? What was the rationale for this study?

"A small trial demonstrated that the phosphodiesterase-5 inhibitor sildenafil improved filling pressures and right ventricular function in a cohort of HFpEF patients with pulmonary venous hypertension. This finding led to the phase II trial, Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX), in HFpEF patients (left ventricular ejection fraction [LVEF] >50%) with NYA functional class II or III symptoms, who received sildenafil at 20mg three times daily for 3 months, followed by 60 mg three times daiy for another 3 months, compared with placebo. There was no improvement in functional capacity, quality of life, or other clinical and surrogate parameters."


Compare the findings of TOPCAT and ALDO-DHF studies.

"Conceptually targeting myocardial fibrosis in HFpEF, the large-scale Aldosteonse Antagonist Therapy in Adults with Preserved Ejection Fraction Congestive Heart Failure (TOPCAT) trial has been completed. This trial demonstrated no improvement in the primary composite end-point, but did show a secondary signal of benefit on HF hospitalizations, counterbalanced, however, by an increase in adverse effects, particularly hyperkalemia. However, pessimism has been generated by the negative outcome of the Alodsteronse Receptor Blockade in Diastolic Heart Failure (ALDO-DHF) study wherein spironolactone improved echocardiographic indices of diastolic dysfunction but failed to improve exercise capacity, symptoms, or quality-of-life measures."


What might the usefulness of LCZ696 in patients with HFpEF?

"A unique molecule that hybridez an ARB with an endopeptidase inhibitor, LCZ696, increases the generation of myocardial cyclic guanosine 3',5'-monophospahte, enhances myocardial relaxation, and reduces ventricular hyeprtrophy. This dual blocker has been shown to reduce circulating natriuretic peptides and reduce left atrial size to a significantly greater extent than valsartan alone in patients with HFpEF."


Some investigators have suggested that the exercise intolerance in HFrEF is a manifestation of chrotropic insuffiiency and that such aberrations could be corrected with use of rate responsive pacemakers, but this remains an inadequately investigated contention.
True or False?

The argument applies only for those with HFpEF.


Summarize the epidemiology of ADHF regarding short- and long-term mortality, as well as major events incidence at 12 months after hospitalization.

"Admission with a diagnosis of ADHF is associated with excessive morbidity and mortality, with nearly half of these patients readmitted for management with 6 months, and a high short-term (5-8% in-hospital) and long-term mortality (20% at 1 year). Importantly, long-term aggregate outcomes remain poor, with a combined incidence of cardiovascular deaths, heart failure hospitalizations, myocardial infarction, strokes, or sudden deaths, heart failure hospitalizations, myocardial infarction, strokes, or sudden death reaching 50% at 12 months after hospitalization."


Name all the precipitant factors known to be associated with decompensation of chronic HF.

"The first principle of managemnt of [ADHF] patients is to identify and tackle down precipitants of decompensation. Identification and management of medication nonadherence and use of prescribed medicines such as nonsteroidal anti-inflammatory drugs, cold and flu preparations with cardiac stimulants, and herbal preparations, including licorice, ginseng, and ma huang (an herbal form of ephedrine now banned in most places), are required. Active infection and overt or covert pulmonary thromboembolism should be sought, identified, and treated when clinical clues suggest such direction. When possible, arrhythmias should be corrected by controlling heart rate or restoring sinus rhythm in patients with poorly tolerated rapid atrial fibrillation and by correcting ongoing ischemia with coronary revascularization or by correcting offenders such as ongoing bleeding in demand-related ischemia."


The routine use of pulmonary artery catheter is not recomended in those with ADHF and should be restricted to those who respond poorly to diuresis or experience hypotension or signs and symptoms suggestive of a low cardiac output where therapeutic targets are unclear.
True or False?



Name the parameters associated with worser outcomes in those with hospitalization due to ADHF.

Blood urea nitrogen >43mg/dL, systolic blood pressure less than 115 mmHg, serum creatinine level >2,75mg/dL, and elevated troponin I level.


Digoxin might reduce hospitalizations in those with HFpEF.
True or False?

Although this result has not been shown in the mentioned subset DIG trial. It is mentioned in the therapeutic algorithm for HFpEF.


What is the best diuretic regimen for those admitted with ADHF?

"Randomized clinical trials of high-versus low-dose or bolus versus continuous infusion diuresis have not provided clear justification for the best diuretic strategy in ADHF, and as such, the use of diuretic regimnes remains an art rather than science."


Which diuretic is most commonly used in those with ADHF?

"Addition of a thiazide diuretic agent such as metolazone in combination provides a synergistic effect and is often required in patients receiving long-term therapy with loop diuretic agents."


How should one monitorize patients with ADHF regarding their volemic status and optimal euvolemia achievement for discharge planning?

"Physical examination findings, speifically the jugular venous pressure coupled with biomarker trends, are useful in timing discharge planning."


Summarize the definition, incidence and pathophysiology of cardiorenal syndrome.

"The cardiorenal syndrome is being recognized increasingly as a complication of ADHF. Multiple definitions have been proposed for the cardiorenal syndrome, but at its simplest it can bge thought to reflect the interplay between abnormalities of heart and kidney function, with deteriorating function of one organ while therapy is administered to preserve the other. Approximately 30% of patients hospitalized with ADHF exhibit abnormal renal function at baseline, and this is associated with longer hospitalizations and increased mortality. However, mechanistic studies have been largely unable to find correlation between deterioration in renal function, cardiac ouput, left-sided filling pressures, and reduced renal perfusion; most patients with cardiorenal sndrome demonstrate a preserved cardiac output. It is hypothesized that in patients with established heart failure, this syndrome represents a complex interplay of neurohormonal factors, potentially exacerbated by "backward failure" resulting from increased intra-abdominal pressure and impairment in return of renal venous blood flow. Continued use of diuretic therapy may be associated with a reduction in glomerular filtration rate and a worsening of the cardiorenal sydrome when right-sided filling pressures remain elevated."


Inotropic therapy in those with late stages of HF has been shown to preserve or improve renal function in selected individuals in the short term.
True or False?



Summarize the rationale of using ultrafiltration in patients with ADHF, as well as the evidence available for this therapy.

"Ultrafiltration (UF) is an invasive fluid removal technique that may supplement the need for diuretic therapy. Proposed benefits of UF include controlled rates of fluid removal, neutral effects on serum electrolytes, and decreased neurohormonal activity. This technique has also been referred to as aquapheresis in recognition of its electrolyte depletion-sparing effects. Current UF systems function with two large-bore, peripherally inserted venous lines. In a pivotal study evaluating UF versus conventional therapy, fluid removal was improved and subsequent heart failure hospitalizations and urgent clinic vists were reduced with UF, however, no improvement in renal function and no subjective differences in dyspnea scores or adverse outcomes were noted. More recently, in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial, 188 patiets with ADHF and worsening renal failure were randomized to stepped pharmacologic care or UF. The primary endpoint was a change in serum creatinine and change in weight (reflecting fluid removal ) at 96 hours. Although similar weight loss occurred in both groups (approximately 5,5 Kg) there was worsening in creatinine in the UF group. Deaths and hospitalizations for heart failure were no different between groups, but there were more severe adverse evets in the UF group, mainly due to kidney falure, bleeding complications, and intravenous catheter-related complications."


What are the main results of the ASCEND-HF trial? What was the rationale for this study?

"[Nesiritide] was introduced in a fixed dose for therapy after a comparison with intravenous nitrates suggested more rapid and greater reduction in pulmonary capillary wedge pressure. Enthusiasm for nesiritide wanned due to concerns within the pivotal trials for development of renal insufficiency and an increase in mortality. To address these concerns, a large-scale morbidity and mortality trial, the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) study was completed in 2011 and randomly enrolled 7141 patients with ADHF to nesiritide or placebo for 24 to 168 hours in addition to standard care. Nesiritide was not associated with an increase or a decrease in the rates of death and rehospitalization and had a clinically insignigificant benefit on dyspnea. Renal function did not worsen, but increased rates of hypotension were noted. Although this trial established the safety for this drug, the routine use cannot be advocated due to lack of significant efficacy."


Summarize the evidence regarding serelaxin.

"Recombinant human relaxin-2, or serelaxin, is a peptide upregulated in pregnancy and examined in ADHF patients with a normal or elevated blood pressure. In the Relaxin in Acute Heart Failure (RELAX-AHF trial), serelaxin or placebo was added to a regimen of standard therapy in 1161 patients hospitalized with ADHF, evidence of congestion, and systolic pressure >125 mmHg. Serelaxin improved dyspnea, reduced signs and symptoms of congestion, and was associated with less early worsening of HF. Exploratory endpoints of hard outcomes at 6 months suggest positive signals in favor of mortality reduction."


Compare dobutamine to milrinone.

Both are inotropic therapies that act via direct or indirect pathways, more specifically, dobutamine is a sympathomimetic amine while milrinone is a phosphodiesterase-3 inhibitor. "Their activity leads to an increase in cytoplasmic calcium. Inotropic therapy in those with a low-output state augments cardiac output, improves perfusion, and relieves congestion acutely. Although milrinone and dobutamine have similar hemodynamic profiles, milrinone is slower acting and is renally excreted and thus requires dose adjustments in the setting of kidney dysfunction. Since milrinone acts downstream from the b1-adrenergic receptor, it may provide an advantage in patients receiving beta blockers when admitted to the hospital."


Studies are in agreement that long-term inotropic therapy increases mortality, while short-term usage is also associated with increased arrhythmia, hypotenson, and no beneficial effects on hard outcomes.
True or False?



Compare the RELAX study to RELAX-AHF.

- RELAX: this study randomized patients to sildenafil versus placebo. Patients on the sildenafil arm were taking 20mg three times a day for 3 months and 60mg three times a day in the following 3 months. No differences on outcomes were shown (namely quality-of-life measurements, as well as surrogate outcomes);
- RELAX-AHF: this study enrolled patients with ADHF, congestive symptoms and systolic pressure >125mmHg,
taking seralaxin (recombinant human relaxin-2). Patients on seralaxin had improvement on dyspnea, reduzed signs and symptoms of congestion, and less early worsening of HF. Exploratory endpoints of hard outcomes at 6 months suggested positive signals in favor of mortality reduction.


What are the main results of the REVIVE II and SURVIVE trials?

"Two trials, the second Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy (REVIVE II) and Survival of Patients with Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE), have tested [levosideman] in ADHF. SURVIVE compared levosimendan with dobutamine, and despite an initial reduction in circulating B-type natriuretic peptide levels in the levosimendan group compared with patients in the dobutamine group, this drug did not reduce all-cause mortality at 180 days or affect any secondary clinical outcomes. The second trial compared levosimendan against traditional noninotropic therapy and found a modest improvement in symptoms with worsened short-term mortality and ventricular arrhythmias."


What are the main findings of the ATOMIC-HF study?

"Another drug that functions as a selective myosin activator, omecamtiv mecarbil, prolongs the ejection and increases fractional shortening. Distinctively, the force of contraction is not increased, and as such, this agent does not increase myocardial oxygen demand. In a 600-patient trial called ATOMIC-HF (A Trial of Omecamtiv Mecarbil to Increase Contractility in ACute Heart Failure), this agent showed improvement in dyspnea scores in the highest dose cohort, but no across all enrolled patients."


Summarize the findings of PROTECT and EVEREST trials.

"The Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) trial of selective adenosine antagonism and the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial of an oral selective vasopressin-2 antagonist in ADHF were both negative with respect to hard outcomes."


Individuals with a lower exposure to ACE inhibitors and beta blockers due to inability to tolerate optimal doses represent a high-risk cohort with poor prognosis.
True or False?



State the reduction in mortality and hostapitalizations in patients taking ACE inhibitors in HFrEF, as well as those in whom beta blockers are added. Which patients might not tolerate these pharmacological groups?

"Meta-analysis suggest a 23% reduction in mortality and a 35% reduction in the combination endpoint of mortality and hostpailizations for heart failure in patients treated with ACEis. Patients treated with beta blockers provide a further 35% reduction in mortality on top of the benefit provided by ACEis alone. Increased experience with both agents in a broad range of patients with HFrEF has demonstrated the safety of ACEis in treating patients with mild renal insufficiency and the tolerability of beta blockers in patients with moderately controlled diabetes, asthma, and obstructive lung disease."


ACEis exert their beneficialeffects as a class, contrasting with beta blockers.
True or False?

"ACEis exert their beneficial effects in HFrEF as class; however, the beneficial effects of beta blocker sare thought to be limited to speific drugs. Beta blockers with intrinsic sympathomimetic activy (xamoterol) and other agents, including bucindolol, have not demonstrated a survival benefit. On the basis of investigations, beta blocker use in HFrEF should be restricted to carvedilol, bisoprolol, and metoprolol succinate - agents tested and proven to improve survival in clinical trials."


What are the main findings of the CIBIS III Trial?

"Wheter beta blockers or ACEis should be started first was answered by the Cardiac Insufficiency Bisoprolol Study (CIBIS) III, in which outcomes did not vary when either agent was initiated first. Thus, it matters little which agent is initiated first; wat does matter is that optimally titrated doses of both ACEis and beta blockers be estabilshed in a timely manner."


How should one titrate ACEis and beta blockers in HF? What are the advantagens of the updosing?

"A trial has indicated that higher tolerated doses of ACEis achieve greater reduction in hostapilizations without materially improving survival. Beta blockers demonstrate a dose-dependent improvement in cardiac function and reductions in mortality and hospitalizations. Clinical experience suggests that, in the absence of symptoms to suggest hypotension (fatigue and dizziness), pharmacotherapy may be up-titrated every 2 weeks in hemodynamically stable and euvolemic ambulatory patients as tolerated."


Summarize the evidence of mineralocorticoid antagonists in HFrEF.

"Aldosterone antagonism is associated with a reduction in mortality in all stages of symptomatic NYHA class II to IV HFrEF. Elevated aldosterone levels in HFrEF promote sodium retention, electrolyte imbalance, and endothelial dysfunction and may directly contribute to myocardial fibrosis. The selective agent eplerenone (tested in NYHA class II and post-myocardial infarction heart failure) and the nonselective antagonist spironolactone (tested in NYHA class III and IV heart failure) reduce mortality and hospitalizations, with significant reductions in sudden cardiac death. Hyperkalemia and worsening renal function are concerns, especially in patients with underlying chronic kidney disease, and renal function and serum potassium levels must be closely monitored."


The initial strategy in HFrEF should be a two-drug combination first (ACEi and beta blocker; if beta blocker intolerant, then ACEI and ARB; if ACEI intolerant, then ARB and beta blocker).
True or False?



Summarize the findings of VAL-HEFT and ASTRONAUT trials.

"The Valsartan Heart Failure Trial (Val-HEFT) suggested that addition of valsartan in patients already receiving treatment with ACEIs and beta blockers was associated with a trent toward worse outcomes."
"A recent trial called the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) tested a direct renin inhibitor, aliskiren, in addition to other heart failure medications, within a week after discharge from a hospitalization for decompensated HFrEF. No significant difference in cardiovascular death or hostapilization at 6 or 12 months was noted. Aliskiren was associated with a reduction in circulating natriuretic peptides, but any disease-modifying effect was overcome by excessive adverse events including hyperkalemia, hypotension, and renal dysfunction."


Summarize the pharmacological properties and evidence of the usage of the combination of hydralazine and nitrates in those with HF, including the main findings of the A-Heft study.

"The combination of hydralazine and nitrates has been demonstreated to improve survival in HFrEF. Hydralazine reduces systemic vascular resistance and induces arterial vasodilatation by affecting intracellular calcium kinetics; nitrates are transformed in smooth muscle cells into nitric oxide, which stimulates cyclic guanosine monophosphate production and consequent arterial-venous vasodilation. This combination improves survival, but not to the magnitude evidenced by ACEIs or ARBs. However, in individuals with HFrEF unable to tolerate renin-angiotensin-aldosterone-based therapy for reasons such as renal insufficiency or hyperkalemia, this combination is preferred as a disease-modifying approach. A trial conducted in self-identified African Americans, the African-American Heart Failure Trial (A-Heft), studied a fixed dose of isosorbide dinitrate with hydralazine in patients with advanced symptoms of HFrEF who were receiving standard background therapy. This study demonstrated benefit in survival and hospitalization recidivism in the treatment group. Adherence to this regimen is limited by the thrice-daily dosing schedule."


What are the main findings and limitations of the SHIFT study?

"The Systolic Heart Failure Treatment with Ivabradine Compared with Placebo Trial (SHIFT) was conducted in patients with class II or III HFrEF, a heart rate >70 beats/min, and history of hospitalizations for heart failure during the previous year. Ivabradine reduced hostapilizations and the combined andpoint of cardiovascular-related death and heart failure hostapilization. The study population was not necessarily representative of North American patients with HFrEF since, with a few exceptions, most did not receive internal cardioverter-defibrillation or cardiac resynchronization therapy and 40% did not receive a mineralocorticoid receptor antagonist. Although 90% received beta blockers, only a quarter were on full doses."


Specify the recommendations for ivabradine therapy in those with HFrEF.

"In the 2012 European Society of Cardiology guidelines for the treatment of heart failure, ivabradine was suggested as a second-lie therapy before digoxin is considered in patients who remain symptomatic after guideline-based ACEIs, beta blockers, and mineralocorticoid receptor antagonists and with residual heart rate >70 beats/min. Another grop in whom potential benefit may be expected includes those unable to tolerate beta blockers."


Summarize the pharmacological targets, evidence and recommendations for digoxin therapy in those with HFrEF, as well as the main findings of the DIG trial.

"Digitalis glycosides exert a mild inotropic effect, attenuate carotid sinus baroreceptor activity, and are sympathoinhibiory. These effects decrease serum norepinephrine levels, plasma renin levels, and possibly aldosterone levels. The DIG trial demonstrated a reduction in heart failure hostapilizations in the treatment group but no reduction in mortality or improvement in quality of life. Importantly, treatment with digoxin resulted in a higher mortality rate in women than men. Furthermore, the effects of digoxin in reducing hospitalizations were lower in women than men. Furthermore, the effects of digoxin in reducing hospitalizations were lower in women than in men. It should be noted that low doses of digoxin are sufficient to achieve any potentially beneficial outcomes, and higher doses breah the therapeutic safety index. Although digoxin levels should be checked to minimize toxicity and although dose reductions are indicated for higher levels, no adjustment is made for low levels. Generally, digoxin is now relegated as therapy for patients who remain profoundly symptomatic despite optimal neurohormonal blockade and adequate volume control."


Which calcium channel blockers might be useful or deleterious in those with HFrEF?

"Amlodipine and felodipine, second-generation calcium channel-blocking agents, safely and effectively reduce blood pressure in HFrEF but do not affect morbidity, mortality, or quality of life. The first-generation agents, including verapamil and diltiazem, may exert negative inotropic effects and destabilize previously asymptomatic patients. Their use should be discouraged."


Bosentan is associated with better outcomes in HFrEF.
True or False?

"the endothelin antagonist bosentan is associated with worsening heart failure in HFrEF despite demonstrating benefits in right-sided heart failure due to pulmonary arterial hypertension."


Moxonidine, a centrally acting sympatholytic agent worsens outcomes in left heart failure.
True or False?



What were the main findings of the OVERTURE trial?

"The combined drug omapatrilat hybridizes an ACEI with a neutral endopeptidase inhibitor, and this agent was tested in the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE) trial. This drug did not favorably influence the primary outcome measure of the combined risk of death or hospitalization for heart failure requiring intravenous treatment. The risk of angioedema was notably higher with omapatrilat than ACEIs alone."


Summarize the evidence regarding anti-inflammatory drugs in HFrEF, including the main findings of the ACCLAIM-HF trial.

"Targeting inflammatory cytokines such as tumor necrosis factor alpha by using anticytokine agents such as infliximab and etanercept has been unsuccessful and associated with worsening heart failure. Nonspecific immunomodulation has been tested in the large Advanced Chronic Heart Failure Clinical Assessment of Immune Modulation Therapy (ACCLAIM-HF) trial of 2426 HFrEF patients with NYHA functional class II to IV symptoms. Ex vivo exposure ofa blood sample to controlled oxidative stress initiates apoptosis of leukocytes soon after intramuscular gluteal injection of the treated sample. The physiologic response to apoptotic cells results in a reduction in inflammatory cytokine production and upregulation of anti-inflammatory cytokines. This promising hypothesis was not proven, although certain subgroups (those with no history of previouos myocardial infarction and thse with mild heart failure) showed signals in favor of immunomodulation. Use of intravenous immunoglobulin therapy in noninschemic etiology of heart failure has not been shown to results in beneficial outcomes."


Statins might theoretically be detrimental by depleting ubiquitone in the electron transport chain in those with HF.
True or False?



Summarize the findings of the CORONA and GISSI-HF trials.

"Two trials, controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) and Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiac (GISSI-HF), have tested low-dose rosuvastatin in patients with HFrEF and demonstrated no improvement in aggregate clinical outcomes. If statins are required to treat progressive coronary artery disease in the background setting of heart failure, then they shouyld be employed. However, no rationale appers to exist for routine statin therapy in nonischemic heart failure."


What are the main findings of the WARCEF trial?

"In the alrge Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial, 2305 patients with HFrEF were randomly allocated to either full-dose aspirin or international normalized radio-controlled warfarin with follow-up for 6 years. Among patients with reduced LVEF who were in sinus rhythm, there was no significant overall difference in the primary outcom, betwwen treatment with warfarin and treatment with aspirin. A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage."


Which micronutrients deficiency might result in HF?

Thiamine and selenium.


Thiamine suplpementation might improve cardiac function in those with HFrEF but not ADHF.
True or False?



Summarize the evidence regarding the use of enchanced external counterpulsation (EECP) therapy, as weel as the findings in the PEECH trial.

"Peripheral lower extremity therapy using graded external pneumatic compression at high pressure is administered in 1-hour sessions for 35 treatments (7 weeks) and has been proposed to reduce angina symptoms and extend time to exercise-induced ischemia in patients with coronary artery disease. The Prospective Evaluation of Enchanced External Counterpulsation in Congestive Heart Failure (PEECH) study assessed the benefits of enchanded external counterpulsation in the treatment of patients with mild-to-moderate heart failure. This randomized trial improved exercise tolerance, quality of life, and NYHA functional classification but without an accompanying incrase in peak oxygen consumption. A placebo effect due to the nature of the intervention simply cannot be excluded."


Summarize the recommendations and evidence regarding exercise in HF, as well as the main findings of the HF-ACTIOn study.

"The Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study investigated short-term (3-month) and long-term (12-month) effects of a supervised exercise training program in patients with moderate HFrEF. Exercise was safe, improved patients' sense of well-being, and correlated with a trend toward mortality reduction. Maximal changes in 6-minute walk distance were evident at 3 months with significant improvements in cardiopulmonary exercise time and peak oxygen consumption persisting at 12 months. Therefore, exercise training is recommended as an adjunctive treatment in patients with heart failure."


Name 4 comorbidities frequent in those with HF whose therapy might be associated with better outcomes.

Sleep-disordered breathing, anemia, depression and atrial arrhythmias.


What are the indicators of sleep-disordered breathing (as well as thromboembolism or pulmonary hypertension) accompanying left HF?

Difficult to control hypertension and worsening of right heart function despite an improvement of left ventricular function after medical therapy.


Treatment with nocturnal positive airway pressure improves oxygenation, LVEF, and 6-minute wal distance but there is no conclusive data regarding major outcomes.
True or False?



Summarize the findings of FAIR-HF and RED-HF trials.-

FAIR-HF: "Intravenous iron using either iron sucrose or carboxymaltose (Ferric Carboxymaltose Assessment in Patients with Iron Deficiency and Chronic Heart Failure [FAIR-HF] trial] has been shown to correct anemia and improve functional capacity."
RED-HF: "Erytroopoiesis-regulatint agents such as erythropoietin analogues have been studied with diswappointing results. The Reuction of Events by Darbepoetin Alfa in Heart Failure (RED-HF) evaluated 2278 mild-to-moderate anemia patients with HFrEF and demonstrated that treatment with darbepoetin alfa did not improve clinical outcomes in patients with systolic heart failure."


What is the prevalence of depression in HF?

One in five patients.


What are the main findings of SADHART-CHF trial?

"the Setraline Against Depression and Heart Disease in Chron ic Heart Failure (SADHART-CHF) trial, showed that sertraline was safe, but did not provide greater reduction in depression or improve cardiovascular status among patients with heart failure and depression compared with nurse-driven multidisciplinary management."


Which pharmacotherapies might be used in atrial fibrillation in congestive heart failure?

Amiodarone and dofetilide.


What is the evidence regarding the use of dronedarone in those with atrial fibrillation and heart failure? Mention the ANDROMEDA study.

"The Antiarrhythmic Trial with Dronedarone in Moderate-to-Severe Congestive Heart Failure Evaluating Morbidity Decrease (ANDROMEDA) studied the effects of the novel antiarrhythmic agent dronedarone and found an increased mortability due to worsening heart failure."


Catheter ablation and pulmonary vein isolation appear to be safe and effective in high-risk cohort HF and compare favorably with the more established practice of atrioventricular node ablation and biventricular pacing.
True or False?



Which patients are the main candidats for cardiac resynchronization therapy (CRT)? Summarize the supporting evidence for these indications.

QRS>149ms and left bundle branch block.
"The Cardiac Resynchronization in Heart Failure Study (CARE-HF) trial was the first study to demonstrate a reduction in all-cause mortality with CRT placement in patients with HFrEF on optimal therapy with continued moderate-to-severe residual symptoms of NYHA class III or IV heart failure. More recent clinical trials have demonstrated disease-modifying properties of CRT in even minimally symptomatic patients with HFrEF, including the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT) and Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT), both of which sought to use CRT in combination with an implantable defibrillator. Most benefit in mildy symptomatic HFrEF patients accrues from applying this therapy in those with a QRS width of >149 ms and a left bundle branch block pattern."


Name the uncertainties surrounding the use of CRT other than patients with QRS >150ms and left bundle branch block pattern.

"narow QRS dyssynchrony has not proven to be a good target for treatment. Uncertainty surrounds the benefits of CRT in those with ADHF, a predominant right bundle branch block pattern, atrial fibrillation, and evidence of scar in the lateral wall, which is the precise location where the CRT lead is positioned."


Summarize the correlation between sudden cardiac death (SCD) and heart failure, as well as the main therapies and risk markers for stratifying risk.

"SCD due to ventricular arrhythmias is the mode of death in approximately half of patients with heart failure and is particularly proportionally prevelant in HFrEF patients with early stages of the disease. Patients who survive an episode of SCD are considered to be at very high risk and qualify for placement of an implantable cardioverter-defibrillator (ICD). Although primary prevention is challenging, the degree of residual left ventricular dysfunction despite opatimal medical therapy (equal or less than 35%) to allow for adequate remodeling and the underlying etiology (post-myocardial infarction or ischemic cardiomyopathy) are the two single most important risk markers for stratification of need and benefit. Currently, patients with NYHA class II or III symptoms of heart failure and an LVEF less than 35%, irrespective of etiology of heart failure are appropriate candidates for ICD prophylatic therapy. In patients with a myocardial infarction and optimal medical therapy with residual LVEF equal or less than 30% (even when asymptomatic), placement of an ICD is appropriate. In patients with a terminal illness and a predicted life span of less than 6 months or in those with NYHA class IV symptoms who are refractory to medications and who are not canddates for transplant, the risks of multiple ICD shocks must be carefully weighed against the survival benefits. If a patients the QRS criteria for CRT, combined CRT with ICD is often employed."


How does one define hibernating myocardium?

"myocardial tissue with abnormal function but maintainted cellular function"


Summarize the STICH trial findings.

"The Surgical Treatment for Ischemic Heart Failure (STICH) trial enrolled 1212 patients with an ejection fraction of 35% or less and coronary artery disease amenable to CABG and randomly assigned them to medical therapy alone or medical therapy plus CABG. There was no significant difference between groups with respect to primary endpoint of death from any cause. Patients assigned to CABG had lower rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiovascular causes."


Summarize the evidence regarding the use of coronary artery bypass grafting (CABG) in those with HFrEF, namely the STICH trial.

"Revascularizing those with left ventricular failure in the absence of angina remains controversial. The Surgical Treatment for Ischemic Heart Failure (STICH) trial enrolled 1212 patients with an ejection fraction of 35% of less and coronary artery disease amenable to CABG and randomly assigned them to medical therapy alone or medical therapy plus CABG. There was no significant difference between groups with respect to the primary endpoint of death from any cause. Patients assigned to CABG had lower rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiovascular causes."


What is the efficacy of surgical ventricular restoration and ventricular aneurysm exclusion surgery for heart failure?

"Surgical ventricular restoration (SVR), a technique characterized by infarct exlusion to remodel the left ventricle by reshaping it surgically in patients with ischemic cardiomyopathy and dominant anterior left ventricular dysfunction, has been proposed. However, in a 1000-patient trial in patients with HFrEF who underwent CABG alone or CABG plus SVR, the addition of SVR to CABG had no disease-modifying effect. Cardiac symptoms and exercise tolerance improved from baseline to a similar degree in both study groups. SVR resulted in lower left ventricular volumes at 4 months after operation. However, left ventricular aneurysm surgery is still advocated in those with refractory heart failure, ventricular arrhythmias, or thromboembolism arising from an akinetic aneurysmal segment of the ventricle. Other remodeling procedures, such as use of an external mesh-like net attached around the heart to limit further enlargement, have not been showen to provide hard clinical benefits, although favorable cardiac remodeling was noted."


There is no evidence supporting mitral regurgitation (MR) correction in ischemic/functional MR.
True or False?



The cardiomyocite is no longer considered a terminally differentiated cell and possesses regenerative capacity.
True or False?



Discuss the positive results of gene-based therapy.

"Two preliminary pilot trials deliviring cells via an intracoronary approach have been reported. In one, autologous c-kit-positive cells isolated from the atria obtained from patients undergoing CABG were cultured and reinfused. In another, cardiosphere-derived cells grown from endomyocardial biopsy specimens were used. These small trials demonstrated improvements in left ventricular function but require far more work to usher in a clinical therapeutic succes."
"A phase II randomized, double-blind, placebo-controlled trial called CUPID (EFficacy and Safety Study of Genetically Targeted Enzyme Replacement Therapy for Advanced Heart Failure) was completed. This study used coronary arterial infusion of adeno-associated virus type 1 carrying the gene for SERCA2a and demonstrated that natriuretic peptides were decreased, reverse remodeling was noted, and symptomatic improvements were forthcoming."


Summarize the evidence regarding the use of invasive monitoring in heart failure, namely the CHAMPION trial.

"Although routinely advocated, intensive surveillance of weight and vital signs with use of telemonitoring has not decreased hospitalizations. Intrathoracic impedance measurements have been advocated for the identification of early rise in filling pressure and worsened hemodynamics so that preemptive management may be employed. However, this has not been successful and may worsen outcomes in the short term. Implantable pressure monitoring systems do tend to provide signals for early decompensation, and in patients with moderately advanced symptoms, such systems have been showen to provide information that can allow implementation of therapy to avoid hospitalizations as much as 39% (in the CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients [CHAMPION] trial)."


Specify the main differences in HF patients from North America, Eastern Europe and South America.

"In oral pharmacologic therap trial o fHFrEF, patients from southwest Europe have a lower incidence of ischemic cardiomyopathy and those in North America tend to have more diabetes and prior coronary revascularization. There is also regional variation in medication use even after accounting for indication. In trials of ADHF, patients in Eastern Europe tend to be younger, with higher ejection fractions and lower natriuretic peptide levels. Patients from South America tend to have the lowest rates of comorbidities, revascularization, and device use. In contrast, patients from North America have the highest comorbidity burden with high revascularization and device use rates."